Genetic Variation Helped Humans Evolve, Adapt To Climate Changes

New light has been shed on a genetic variation that may have played a key role in human evolution by two studies published by an international group of researchers this week in the journal Cell.

To understand a gene variant that might have helped humans adapt to humid climates, the research team used an animal model, along with whole-genome sequencing data. The findings of these studies could provide a road map to human biological history and modern day variability.

"There is an archaeological record hidden in our DNA that can help point us to the traits that have been critical in human survival, such as resistance to infectious diseases and new abilities to respond to different environments," says Pardis Sabeti of Harvard University and the Broad Institute. "The two studies have uncovered two intriguing human adaptive traits and demonstrate the ability to go from an unbiased genome scan to a novel hypothesis of human evolution."

The first study, led by researchers from Harvard Medical School, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Fudan University and University College London (UCL), revealed that a single genetic mutation of the EDAR gene produced several traits common to East Asian populations such as thicker hair and denser sweat glands. They also modeled the spread of this gene mutation across Asia and North America from its emergence in what is currently central China approximately 30,000 years ago.

"This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans," said Sabeti, associate professor in the Center for Systems Biology and Department of Organismic and Evolutionary Biology at Harvard.

"This paper tells a story about human evolution in three parts," said Cliff Tabin, head of the HMS Department of Genetics. "The mouse model links multiple traits to a single mutation, the related association study finds these traits in humans, and computer models tell us where and when the mutation likely arose and spread."

AN UNKNOWN EVOLUTIONARY ADVANTAGE

The gene was identified as a strong candidate for positive selection in earlier studies by Sabeti's team. Evidence within the genetic code suggests that a possible evolutionary advantage is conferred by the gene, but that advantage remains unknown.

The mutation was located in a gene for ectodyplasin receptor (EDAR), which is part of a signaling pathway known to play a key role in the development of hair, sweat glands, and other skin features. One ancestral version of the gene was found in human populations in Africa and Europe. Most East Asians, however, have a derived variant, EDARV370A, linked to thicker scalp hair and altered tooth shape.

The ectodyplasin pathway is widely studied because it is highly conserved across vertebrates — the same genes do the same thing in humans, mice and zebrafish — and because the effect it has on skin, hair and scales can be observed directly.

Yana Kamberov, HMS research fellow in genetics, believed that because of this evolutionary conservation, EDARV370A would exert a similar biological effect in an animal model as in human beings.

Kamberov developed a mouse model with the exact mutation of EDARV370A. This variant is different by one DNA letter from the original population. The mutated mouse manifested thicker hair, more densely branched mammary glands and an increased number of sweat, or eccrine, glands.

"This not only directly pointed us to the subset of organs and tissues that were sensitive to the mutation, but also gave us the key biological evidence that EDARV370A could have been acted on by natural selection," Kamberov said.

This led the scientists to look for similar traits in human populations. A team from Fudan examined the fingertips of Chinese volunteers at colleges and farming villages. They discovered that the sweat glands of the Han Chinese, who carry a derivative variant of the gene, were packed about 15 percent more densely than those found in a control population with the ancestral variant.

The Fudan team collaborated with scientists at UCL to zero in on when and where the genetic mutation emerged. Their computer models suggested that the variation arose in central China between 13,175 and 39,575 years ago, with a median estimate of 30,925 years. This led the team to estimate the age of the derived variant to be at least 15,000 years old. This predates the migration of Native Americans - who also carry the mutation - from Asia.

A COMPLICATED EVOLUTIONARY STORY

The researchers say that the time span suggests different traits could have been under selection at different times. The mutation's many effects, known as pleiotropy, complicate the question. If, for example, changes to sweat glands conferred advantages in new climates at one point, then changes to hair and mammary glands could have conferred other advantages at other times.

"When Pardis started this work, I would not have predicted that a gene that makes good hair would top of a list of mutations that confer evolutionary advantage among humans," said Bruce Morgan, HMS associate professor of dermatology at Massachusetts General Hospital. "However, in this case 'good hair' may have a biological meaning because it is genetically linked to a physiologically adaptive trait like increased sweating capacity. A cultural preference for a physically obvious trait like hair type could have arisen because individuals with it were more successful, and this would help increase selection on the new variant."

"That (pleiotropy) makes it harder for us to make a guess," Sijia Wang, a former UCL PhD student, said. "If there were only one associated trait, we could say with confidence that's where the selective advantage comes from. But with many traits, we don't know which is the target of selection, and which are just hitchhiking."

In his new role, as a Max Planck independent research group leader in dermatogenomics at the Chinese Academy of Sciences — Max Planck Partner Institute for Computational Biology in Shanghai — Wang intends to focus on this question.

Professor Professor Mark Thomas, UCL Research Department of Genetics, Evolution and Environment, said, "We don't know which of the many traits were advantageous in the past. It is easy to imagine that thicker hair, tooth shape, more sweat glands or some other associated skin features could have increased fitness, but for quite different reasons."

Dr Pascale Gerbault, a PhD student in Professor Thomas's group, said, "What seems unlikely is that the same traits were advantageous throughout the whole of the last 30,000 years; prior to 10,000 years ago the climate was cold and highly variable, but for the last 10,000 years it has been much warmer and relatively stable."

The diverse fields of research of the scientists involved in this study allowed the team to begin piecing together the foundation for understanding how select mutations like EDARV370A have impacted human diversity. This is only the beginning, however, according to the team.

"These findings point to what mutations, when, where and how," said Daniel Lieberman, a professor of human evolutionary biology at Harvard University and a co-senior author on the study. "We still want to know why."

The second, accompanying study, utilized data from the 1000 Genome Project to analyze DNA sequence variations across the entire genome. The team identified hundreds of gene variants that show potential for contribution to the human evolutionary adaptation. A mutation in the TLR5 gene, for example, changed the immune responses of cells exposed to bacterial proteins, suggesting that this variant could confer a fitness advantage by protecting against bacterial infections.

The team created a comprehensive list of possible adaptive mutations that drive recent human evolution, which provides groundwork for future research.

The two studies together represent a decisive shift for the field of evolutionary genomics, transitioning from hypothesis-driven to hypothesis-generating science. It is possible to elucidate distinct mechanisms of evolution by moving from genome-wide scans to the characterization of adaptive mutations.

"These two studies are the product of work done in this area for over a decade but can only now be made possible with the major breakthroughs in genomic technology," Sabeti says. "I am struck by the ability of genomics to uncover the secrets of human history."